Perampanel Blocks Transsynaptic α-Synuclein Propagation and Neurodegeneration in a Mouse Model of Lewy Body Disease.

BACKGROUND: Transsynaptic α-synuclein propagation plays a crucial role in the progression of Lewy body disease. We previously demonstrated that an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, perampanel, blocks neuronal uptake of α-synuclein preformed fibrils (PFFs) in an activity-dependent manner. OBJECTIVES: We aimed to elucidate the underlying mechanisms of this effect and whether perampanel inhibits transsynaptic α-synuclein propagation. METHODS: Neuronal uptake of PFFs was evaluated in mouse primary hippocampal neurons using PFFs labeled with pH-sensitive dye. The levels of dynamin1 and phosphorylated dynamin1 were analyzed in wild-type mice treated with perampanel using western blotting. The time course of clearance of PFFs injected into the olfactory bulb was examined in Snca knockout mice. α-Synuclein pathology and neurodegeneration were evaluated in PFF-injected A53T BAC-SNCA transgenic mice with perampanel or vehicle treatment for 2 and 9 months after the removal of injected PFFs. RESULTS: Neuronal uptake of PFFs was blocked by a dynamin inhibitor but not by a clathrin inhibitor in vitro. Oral administration of perampanel significantly increased the level of phosphorylated dynamin1 in mouse brains, suggesting that perampanel suppresses dynamin-dependent endocytosis in vivo. PFFs injected into the olfactory bulb disappeared within 1 week. In A53T BAC-SNCA transgenic mice injected with PFFs, perampanel treatment starting 1 week after PFFs injection reduced the amount of α-synuclein pathology in second- or higher-order regions, but not in first-order regions, from the injection site and ameliorated neurodegeneration. CONCLUSIONS: Perampanel could be a disease-modifying drug for Lewy body disease that modulates transsynaptic α-synuclein propagation, presumably by suppressing dynamin-dependent endocytosis. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.